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Abstract
Glutathione peroxidase 3 is a selenium-dependent enzyme playing a critical role in detoxifying reactive oxidative species and maintaining the genetic integrity of mammalian cells. In this report, we found that the expression of glutathione peroxidase 3 (GPx3) was widely inactivated in prostate cancers. Complete inactivation of GPx3 correlates with a poor clinical outcome. Deletions (hemizygous and homozygous) of GPx3 gene are frequent in prostate cancer samples, occurring in 39% of the samples studied. The rate of methylation of the GPx3 exon 1 region in prostate cancer samples reaches 90%. Overexpression of GPx3 in prostate cancer cell lines induced the suppression of colony formation and anchorage-independent growth of PC3, LNCaP, and Du145 cells. PC3 cells overexpressing GPx3 reduced invasiveness in Matrigel transmigration analysis by an average of 2.7-fold. Xenografted PC3 cells expressing GPx3 showed reduction in tumor volume by 4.8-fold, elimination of metastasis (0/16 versus 7/16), and reduction of animal death (3/16 versus 16/16). The tumor suppressor activity of GPx3 seems to relate to its ability to suppress the expression of c-met. The present findings suggest that GPx3 is a novel tumor suppressor gene.
Highlights
Prostate cancer is one of the leading causes of deaths for men in the United States [1, 2]
glutathione peroxidase 3 (GPx3) (62% versus 24%, P < 0.0001; Fig. 2C). These results suggested an inverse correlation between the progression of prostate cancer and the expression of GPx3
The mechanism of GPx3-mediated tumor suppression is probably related to its ability to down-regulate the expression level of c-met, a tumor-transforming gene. c-met is a receptor tyrosine kinase responsible for a Survival of cells depends on the balance of reactive oxidative species, which was generated from metabolism or from exposure to a harmful environment
Summary
Prostate cancer is one of the leading causes of deaths for men in the United States [1, 2]. The clinical detection rate of prostate cancer has been increased steadily due to the much improved detection of micro-adenocarcinomas in the prostate gland. Many of these prostate cancers are very slow growing and are likely not to be clinically relevant for many patients, nearly 30,000 patients die of prostate cancer annually [1, 2]. Our recent comprehensive gene expression analysis study of prostate cancer tissue revealed that the expression levels of 671 genes and expressed sequence tags (ESTs) were significantly altered in prostate cancer tissues relative to control tissues [3]. We identified that one of the consistently down-regulated genes, called glutathione peroxidase 3 (GPx3), located in 5q23, was
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